Our Program focuses on the determinants of cardiac rhythm and arrhythmias in the neonate young and adult. The unifying hypothesis is that the normal, postnatal remodeling of myocardium is determined by developmental changes in ion channels and their regulatory mechanisms, providing a unique paradigm that can be applied to prevention and treatment of arrhythmias. The Program goal has three components: to identify the mechanisms for (1) the evolution of repolarization from newborn to adult; (2) developmental and regional changes in pacemaker current governing the heartbeat during health and disease; and (3) the modulation of repolarization and rate by the autonomic nervous system and angiotensin II. Our research incorporates electrophysiological, pharmacological, biophysical and molecular techniques to study intact animals, isolate tissues, single cells and sub-cellular components. Projects 1 and 2 are concerned with repolarization. Project 1 considers developmental changes in repolarization at the level of intact animal through ion channels, the modulatory role of the sympathetic nervous system and angiotensin II and the proarrhythmic potential of the developmental changes that occur. Project 2's interest is in the molecular determinants of I-to, particularly in its alpha and beta subunits as determinants of the transmural gradient of repolarization. Projects 3 and 4 concentrate on the pacemaker current, I-f. Project 3 studies alpha and beta subunit contributions to the expression of I-f in sinus node and extra-nodal tissues using normal and mutant isoforms. Project 4 focuses on developmental change and its long-term modulation. The physiologic expression of alpha and beta subunit function is considered in vitro in Project 4 and in vivo by Project 1. Core A provides administrative support; Core B, animal models and biochemical, molecular and statistical support; Core C, cell culture, cell disaggregation and adenoviral constructs. The significance of our research is seen in the concept that an ideal therapy for pathological remodeling would involve its reversal. Given a goal of therapy to reacquire a normal phenotype (and, if appropriate, genotype), the normal developmental remodeling of myocardium is an ideal paradigm: the more we discover about the mechanisms determining this evolution, the more we may be able to apply them to the diseased heart. Hence, we believe that what we learn regarding normal remodeling might be manipulated to prevent/treat arrhythmias.